Stroke is a manifestation of vascular injury to the brain which is commonly secondary to arteriosclerosis or cardiac disease, and is the third leading cause of death (and the second most common cause of neurological disability) in the United States.
Stroke can be categorized into two major types, “ischemic stroke” and “hemorrhagic stroke.” Ischemic stroke encompasses thrombotic, embolic, lacunar and hypo perfusion types of strokes. In contrast to ischemic stroke, hemorrhagic stroke is caused by intracerebral hemorrhage, subarachnoid hemorrhage, and intraventricular hemorrhage, i.e., bleeding into brain tissue, following blood vessel rupture within the brain.
Subarachnoid hemorrhage (SAH) is a condition in which blood collects beneath the arachnoid mater, a membrane that covers the brain. This area, called the subarachnoid space, normally contains cerebrospinal fluid. The accumulation of blood in the subarachnoid space can lead to stroke, seizures, and other complications. Additionally, subarachnoid hemorrhages may cause permanent brain damage and a number of harmful biochemical events in the brain. In some instances, subarachnoid hemorrhages include non-traumatic types of hemorrhages, usually caused by rupture of a berry aneurysm or arteriovenous malformation (AVM). Other causes include bleeding from a vascular anomaly and extension into the subarachnoid space from a primary intracerebral hemorrhage. Symptoms of subarachnoid hemorrhage include sudden and severe headache, nausea and/or vomiting, symptoms of meningeal irritation (e.g., neck stiffness, low back pain, bilateral leg pain) photophobia and visual changes, and/or loss of consciousness.
Subarachnoid hemorrhage is often secondary to a head injury or a blood vessel defect known as an aneurysm. In some instances, subarachnoid hemorrhage can induce a cerebral vasospasm that may in turn lead to an ischemic stroke. A common manifestation of a subarachnoid hemorrhage is the presence of blood in the CSF.
Subjects having a subarachnoid hemorrhage can be identified by a number of symptoms. For example, a subject having a subarachnoid hemorrhage will present with blood in the subarachnoid, usually in a large amount. Subjects having a subarachnoid hemorrhage can also be identified by an intracranial pressure that approximates mean arterial pressure, by a fall in cerebral perfusion pressure or by the sudden transient loss of consciousness (sometimes preceded by a painful headache). In about half of cases, subjects present with a severe headache which may be associated with physical exertion. Other symptoms associated with subarachnoid hemorrhage include nausea, vomiting, memory loss, hemiparesis and aphasia. Subjects having a subarachnoid hemorrhage can also be identified by the presence of creatine kinase-BB isoenzyme activity in their CSF. This enzyme is enriched in the brain but is normally not present in the CSF. Thus, its presence in the CSF is indicative of “leak” from the brain into the subarachnoid. Assay of creatine-kinase BB isoenzyme activity in the CSF is described by Coplin et al. (Coplin, et al, Arch Neurol, 1999, 56(11):1348-1352) Additionally, a spinal tap or lumbar puncture can be used to demonstrate if there is blood present in the CSF, a strong indication of a subarachnoid hemorrhage. A cranial CT scan or an MRI can also be used to identify blood in the subarachnoid region. Angiography can also be used to determine not only whether a hemorrhage has occurred but also the location of the hemorrhage.
Subarachnoid hemorrhage commonly results from rupture of an intracranial saccular aneurysm or from malformation of the arteriovenous system in, and leading to, the brain. Accordingly, a subject at risk of having a subarachnoid hemorrhage includes subjects having a saccular aneurysm as well as subjects having a malformation of the arteriovenous system. It is estimated that 5% of the population have such aneurysms yet only 1 in 10,000 people actually have a subarachnoid hemorrhage. The top of the basilar artery and the junction of the basilar artery with the superior cerebellar or the anterior inferior cerebellar artery are common sites of saccular aneurysms. Subjects having a subarachnoid hemorrhage may be identified by an eye examination, whereby slowed eye movement may indicate brain damage. A subject with a developing saccular aneurysm can be identified through routine medical imaging techniques, such as CT and MRI. A developing aneurysm forms a mushroom-like shape (sometimes referred to as “a dome with a neck” shape).
Among patients who suffer SAH and survive the initial ictus, vasospasm remains the most feared medical complication. A vasospasm is a sudden decrease in the internal diameter of a blood vessel that results from contraction of smooth muscle within the wall of the vessel. Vasospasms result in decreased blood flow, but increased system vascular resistance. It is generally believed that vasospasm is caused by local injury to vessels, such as that which results from atherosclerosis and other structural injury including traumatic head injury. Cerebral vasospasm is a naturally occurring vasoconstriction which can also be triggered by the presence of blood in the CSF, a common occurrence after rupture of an aneurysm or following traumatic head injury. Cerebral vasospasm can ultimately lead to brain cell damage, in the form of cerebral ischemia and infarction, due to interrupted blood supply. Cerebral vasospasm can occur any time after rupture of an aneurysm but most commonly peaks at seven days following the hemorrhage and often resolves within 14 days when the blood has been absorbed by the body.
A subject having a vasospasm is a subject who presents with diagnostic markers and symptoms associated with vasospasm. Diagnostic markers include the presence of blood in the CSF and/or a recent history of a subarachnoid hemorrhage. Vasospasm associated symptoms include paralysis on one side of the body, inability to vocalize the words or to understand spoken or written words, and inability to perform tasks requiring spatial analysis. Such symptoms may develop over a few days, or they may fluctuate in their appearance, or they may present abruptly.
MR angiography and CT angiography can be used to diagnose cerebral vasospasm. Angiography is a technique in which a contrast agent is introduced into the blood stream in order to view blood flow and/or arteries. A contrast agent is required because blood flow and/or arteries are sometimes only weakly apparent in a regular MR or CT scan. Appropriate contrast agents will vary depending upon the imaging technique used. For example, gadolinium is a common contrast agent used in MR scans. Other MR appropriate contrast agents are known in the art. Transcranial Doppler ultrasound can also be used to diagnose and monitor the progression of a vasospasm. As mentioned earlier, the presence of blood in the cerebrospinal fluid can be detected using CT scans. However, in some instances where the amount of blood is so small as to not be detected by CT, a lumbar puncture is warranted.
Vasospasm is a frequent source of secondary stroke and the delayed ischemic deficits that usually develop within the first 2 weeks after hemorrhage (Mendelow et al., 1988). At present, there are significant limitations to the treatment of aneurysmal SAH-induced cerebral vasospasm. Current therapeutic options include intracranial angioplasty, triple-H (hypervolemia, hemodilution, and hypertension) therapy, and oral administration of nimodipine as vasospasm prophylaxis. However, because the majority of patients who suffer SAH either die or become permanently disabled, there is substantial room for improvement in treatment strategies for this group of patients (Allen et al., 1983).
Nimodipine was introduced as a therapeutic agent for the prophylaxis of vasospasm based on findings of a small randomized clinical trial in the U.S. (Allen et al., 1983) and a large trial in the United Kingdom (Pickard et al. 1989). Both trials revealed modest improvements in neurological outcomes following nimodipine administration. Although the drug is accepted as the standard of care, the mechanism by which it works remains controversial. In addition to causing vascular relaxation, nimodipine may also serve as a neuroprotectant by blocking early neuronal calcium influx in the setting of acute ischemia (Inzitari et al., 2005; Korenkov et al., 2000). However, despite an improvement in functional outcome, no difference in angiographic vasospasm was observed between treatment and placebo in several trials (Allen et al., 1983; Petruck et al. 1988; Pickard et al. 1989). Thus, new drugs for the effective treatment and prevention of SAH and other cerebral hemorrhages are much desired.